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A. Overview navigator

  1. Platelet Aggregation Pathways
    1. Thrombin
    2. Thromboxane A2
    3. ADP (adenosine diphosphate)
    4. Glycoprotein IIb/IIIa (integrin)
  2. Types of Platelet Blocking Agents
    1. Cyclooxygenase Inhibitors - aspirin (ASA)
    2. Inhibitors of Platelet ADP (P2Y12) Receptors - ticlopidine, clopidogrel [2]
    3. Inhibitors of Platelet Adhesion - glycoprotein IIb/IIIa blockers
    4. Direct thrombin inhibitors - antithrombin, argatroban, ximelagatran
    5. Specific Thromboxane Inhibitors - in development
    6. Unclear Mechanism - dipyridamole (Persantine®)
    7. These agents tend to be more useful for arterial than for venous thromboembolic disease
  3. Other clotting inhibitors
    1. Heparin - enhances antithrombin efficacy
    2. Warfarin - inhibits vitamin K dependent clotting factors
    3. Prostacyclin - blocks platelet aggregation, counteracts TBX A2
    4. Nitric oxide - mediated via increases in cGMP levels

B. Aspirin (ASA) [3,4,8] navigator

  1. Irreversible inhibition of platelet function by acetylation
    1. Low doses block COX-1 only in platelets
    2. Higher doses block COX-1 and COX-2 in platelets and many other cells
    3. COX-1 blockade in platelets leads to blockade of thromboxane A2 (TXA2) synthesis
    4. Prostacyclin (PGI2) is primarily made in endothelial cells through a COX-2 pathway
    5. PGI2 is less susceptible to inhibition by low ASA than is TXA2
    6. COX1 blockade and overall antiplatelet activity of ASA similar in men and women [16]
  2. Dose depends on indication but low doses usually preferred in primary prevention
  3. Overall, ASA (81-160mg po qd) reduced thromboembolic disease >25% [5]
  4. Primary Prevention
    1. In men, reduces cardiovascular events 14% and 32% reduction in myocardial infarction (MI) without effect on stroke at 81mg po qd or 325mg po qod [15,48,72]
    2. In women, primary prevention with 100mg po qod ASA reduced stroke 12-17% but not MI [15,18,72]; note this is a very low dose
    3. Overall stroke risk reduction of 15% for low dose and 9% for high dose (>325mg/d) [6]
    4. ASA 75mg/d improves mortality when added to aggressive HTN treatment [32]
    5. Does not appear to prevent peripheral arterial disease (PAD) [53]
    6. ASA had no benefit compared with placebo in stroke prevention in asymptomatic patients with carotid bruits and >50% carotid stenosis
    7. ASA 1300mg qd superior to warfarin for prevention of events in patients with symptomatic carotid stenosis [21]
    8. ASA was effective in preventing initial strokes in low risk AFib patients [27]
    9. Reduces MI events by 137 per 10,000 person-years in men [38]
    10. Reduces Stroke events by 39 per 10,000 person-years [38]
    11. ASA reduced MI but not stroke in patients with no clinical vascular disease [53]
    12. ASA 100mg po qod reduced stroke risk but not MI risk in primary prevention in women [18]
    13. ASA 81-162mg qd was at least as effective in primary prevention in patients with multiple CAD risks as ASA+clopidogrel, and is safer [19]
    14. ASA at least 300mg qd x 5 years associated with 25% reduced colorectal risk at 10 years [73]
  5. Secondary Prevention [8]
    1. Secondary prevention after MI is usually 325mg po qd (minimum 160mg po qd)
    2. Secondary ischemic stroke prevention doses usually 160-325mg po qd
    3. For chronic stable or for unstable angina, ASA 75mg po qd effective
    4. ASA 325mg po qd reduces risk of need for peripheral artery surgery
    5. ASA 81-162mg qd + clopidogrel 75mg qd is superior to ASA alone for secondary prevention of cardiac events [19]
    6. For polycythemia vera, at least 100mg po qd required to reduce thromboembolic risks
    7. For lone atrial fibrillation, dose is 325mg po qd
    8. Antiplatelet agent use associated with improved survival in heart failure
    9. In black patients, ticlopidine 500mg/d no more effective than ASA 650mg/d [9]
    10. ASA does not reduce claudication
  6. Side Effects
    1. Gastric distress and/or ulceration
    2. Wheezing, asthma attacks, hives
    3. Interstitial nephritis and/or renal insufficiency (prostaglandin inhibition)
    4. Tinitus ("salicylism")
    5. Anaphylaxis - particularly in patients with atopy, nasal polyps (triad asthma)
    6. Risk of neutropenia is ~0.1% [35]
    7. Little cross reaction between ASA allergies and NSAID allergies
    8. Increased bleeding risk
    9. Increases risk of intracranial hemorrhage by 12 events per 10,000 patient-years [38]
    10. ASA+esomeprazole (Nexium®) 20mg qd is safe in patients with previous ASA-induced peptic ulcer bleeding; recurrent bleeding rate 0.7% over 1 year [63]
  7. Benefits of prophylactic ASA therapy outweigh risks in nearly all patients [38]
  8. Whether 325mg po qod is superior to 81mg po qd is not clear at this time [49]
  9. All patients with >3% risk of CAD should be offerred ASA [3,4]
  10. Possible that chronic use of ibuprofen (Advil®) may reduce efficacy of ASA [66,67]
  11. COX-2 selective inhibitor rofecoxib (Vioxx®) 50mg had increased thrombotic events [67]
  12. Diclofenac and naproxen do not appear to have prothrombotic effects
  13. Ibuprofen for 7 days has mild antiplatelet effects which disappear after 24 hours [69]

C. Clopidogrel (Plavix®) [30,31,35] navigator

  1. Thienopyridine that irreversibly inhibts platelet aggregation
    1. Carboxymethyl derivative of ticlopidine, similar in structure and efficacy [2]
    2. Metabolized to active antagonist of P2Y12 (ADP) receptor on platelets
    3. Has at least 10 fold less risk of neutropenia (~0.1%) than ticlopidine [35]
    4. Very low, but reported, risk for TTP in <1 in 20,000 patients [51]
  2. Binds to ADP receptors (adenyl cyclase coupled) on platelet surface
    1. Requires 2-3 days for initiation of platelet blocking effects
    2. After stopping clopidogrel, 8-10 days required for normalization of bleeding time
  3. Indications [19,26]
    1. Approved for secondary prevention of vascular events in patients with atherosclerosis
    2. Primary prevention of stroke in patients with atherosclerosis
    3. Reduces risk of myocardial infarction (MI) in high risk patients who cannot tolerate ASA
    4. Combination with ASA in high risk patients with acute coronary syndromes (ACS) and with stent placement during PCI [30]
    5. Strongly recommended for all secondary prevention, usually with ASA [19]
    6. Generally not recommended for primary prevention in combination with ASA or in stable coronary disease due to increased bleeding risk [19,30]
    7. When combined with ASA, reduces acute cardiovascular events after angioplasty [61,68]
    8. Clopidogrel added to ASA in patients with acute coronary syndromes (ACS) without ST segment elevation reduced cardiovascular events including death by 20% [62]
    9. Clopidogrel added to ASA for acute MI in patients <75 years improves patency and reduces ischemic complications [60]
    10. Clopidogrel 75mg po qd added to standard therapy for MI reduces mortality, reinfarction, stroke [71]
    11. Clopidogrel 600mg (high dose) po 2 hours before elective PCI eliminates benefits of abciximab (a gp2b/3a inhibitor) in mild to moderate risk patients [13]
    12. In patients with PCI or medically treated ACS, discontinuation of clopidogrel was associated with a 1.8X increased risk of death and acute MI within the first 90 days versus the next 90 days [7]
    13. Clopidogrel should not be added to ASA for primary CV prevention [75]
  4. Side Effects
    1. Clopidogrel added to ASA increases major bleeding by 1-1.5% in various studies [26,62]
    2. Clopidogrel added to ASA for primary CV prevention is not helpful and may cause harm [75]
    3. Generally well tolerated with minimal severe side effects (neutropenia ~0.1%)
    4. Risk of rebleeding 8.6%/year in patients who have had a history of ASA-induced peptic ulcer bleeding [63]
    5. As monotherapy, generally has 0.5-1.0% lower risk of major bleeding than ASA [26]
    6. Rash and diarrhea are most common side effects
  5. Dose
    1. For chronic outpatient treatment, loding dose 300mg x 1, then 75mg once per day
    2. For ACS, clopidogrel 300-900mg initially, then 75mg qd should be used
    3. Loading doses of 600-900mg x1 are increasingly recommended in ACS [20]
    4. Clopidogrel is continued for 1 year with benefit after percutaneous coronary interventions (PCI) along with ASA [10]
    5. May be used in combination with ASA or in ASA intolerant patients
    6. Not safe in patients with history of ASA-induced peptic ulcer bleeding (consider combining with proton pump inhibitor or using ASA with proton pump inhibitor) [63]
  6. Should replace ticlopidine in all cases

D. Ticlopidine (Ticlid®) [35] navigator

  1. Clopidogrel has replaced ticlopidine for nearly all applications due to reduced side effects [1]
  2. Like clopidogrel, ticlopidine blocks ADP pathway for platelet activation [2]
    1. Requires 2-3 days for initiation of platelet blocking effects
    2. Peak platelet inhibition in 4-7 days
    3. Maximal overall inhibition of platelet clotting function ~25%
    4. After stopping ticlopidine, 8-10 days required for normalization of bleeding time
  3. Ticlopidine 250mg bid compared with aspirin 650mg bid in TASS [1]
    1. TASS = Ticlopidine - Aspirin Stroke Study
    2. Ticlopidine had 2% fewer non-fatal stroke or any cause death (17% versus 19%)
    3. Ticlopidine had 3% fewer fatal and non-fatal strokes (10% versus 13%)
    4. In black patients, ticlopidine 500mg/d no more effective than ASA 650mg/d for prevention of vascular events after initial stroke [9]
  4. Canadian American Ticlopidine Study (CATS) [36]
    1. Ticlopidine 250mg bid versus placebo in people with completed stroke
    2. Major endpoints included recurrent nonfatal stroke, nonfatal MI, vascular death
    3. Ticlopidine group showed 30% fewer episodes, equal male-female benefit
  5. Side effects include diarrhea and neutropenia
    1. Neutropenia usually occurs after 3-4 weeks on ticlopidine
    2. Neutropenia requires frequent monitoring, about every 2 weeks for 3-6 months
    3. Monthly monitoring for thrombocytopenia (and TTP, see below) after that
  6. Risk of severe neutropenia ~1%
    1. Neutropenia usually reversible with stopping drug
    2. Addition of G-CSF may hasten return of neutrophils
  7. Thrombotic Thrombocytopenic Purpura (TTP)
    1. This severe side effects usually take 3-4 weeks to develop
    2. However, it occurred in 20% of patients within 2 weeks of ticlopidine initiation
    3. Occurred in ~0.02% of patients on ticlopidine (mean time on drug 5-60 days)
    4. Plasmapheresis is strongly recommended
    5. Ticlopidine induces antibodies to vWF processing protein, likely inducing TTP
  8. Clopidogrel should replace ticlopidine in nearly all patients for long term use [31,35]

E. Platelet GPIIb/IIIa Blockers [39,41,52] navigator

  1. Platelet glycoprotein 2b/3a is a member of the integrin family
  2. Integrins are adhesion molecules composed of two chains
  3. GP2b/3a is composed of the alpha IIb chain and the beta IIIa chain
    1. Mature alpha polypeptide composed of 105K heavy and 25K light chains
    2. Mature beta chain is 95K
    3. Integral membrane proteins with large extracellular domains
    4. >60,000 copies on platelet surface
  4. GP2b/3a is related to integrin alpha V beta III (aVß3)
    1. aVß3 is the vitronectin receptor
    2. Expressed at low levels on platelets
    3. Some of the GP2b/3a antibodies cross react with this protein
    4. Abciximab clearly blocks aVßIII function
    5. Peptide and nonpeptide blockers do not appear to block aVß3
  5. Formation of Platelet Plug
    1. Early activation of platelet through various other glycoproteins and integrins
    2. GGP2b/3a is converted from resting to active state after initial platelet stimulation
    3. This conversion is final step in platelet binding to vWF and fibronectin
    4. Activated GP2b/3a also binds to fibronectin, vitronectin, thrombospondin
    5. Blockade of GP2b/3a function therefore inhibits key final step in thrombogenesis
  6. Efficacy proved for intravenous agents in PCI (angioplasty ± stenting) and ACS [42,68]
  7. GPIIb/IIIa Blockers (Tables in References [39,41])
    1. Abciximab (Reopro®) - approved in PCI, ACS
    2. Eptifibatide (Integrilin®) - approved PCI, ACS
    3. Tirofiban (Aggrastat®) - approved only for ACS
    4. YM337 monoclonal (Phase II)
    5. Lamifiban (Phase III)
    6. Fradafiban (Phase II)
    7. Xemilofiban (Phase III, oral)
    8. Orbofiban (Phase III, oral)
    9. Sibrafiban (Xubix®, Phase III, oral)
    10. Roxifiban (Phase II, oral)
    11. Lotrafiban (Phase II, oral)
    12. Lefradifiban (Phase II, oral)
  8. Main adverse event is increased bleeding, minimized with reducing heparin doses

F. Abciximab (ReoPro®) [17,41] navigator

  1. Abciximab (c7E3) is selective for platelet glycoprotein IIb/IIIa
    1. This antibody (Ab) that binds platelet glycoprotein IIb/IIIa
    2. This mouse Fab - human Fc (chimeric) Ab also binds other platelet surface glycoproteins
  2. Blocks platelet adhesion
    1. Platelet gp IIb/IIIa binds to fibrinogen and von Willebrand Factor
    2. Additional effects on P-selectin expression [40]
    3. Very potent anti-platelet activity
    4. Maximal inhibition of platelet function ~80% [35]
    5. Blocks platelets within minutes of administration
    6. Platelet blocking effects persist for 24-48 hours after stopping infusion
  3. Clearly reduces acute closure events during angioplasty ± stenting
    1. Overall 20-30% reduction in 30 day death, MI or emergency procedure for ischemia
    2. Twofold increase in bleeding rates in treated versus placebo group (with normal heparin)
    3. Use of reduced dose, weight adjusted, heparin with qbciximab reduced bleeding but not efficacy in the EPILOG trial [22]
    4. Marked benefit when used in early MI with stenting [59]
    5. Reduced rate of thrombotic complications in ACS patients undergoing PCI
    6. Abciximab with PCI in acute ST-segment MI, improves TIMI Grade III flow, possibly clinical outcomes [12]
    7. Improves initial patency but no effect on restenosis rates in followup evaluation [22]
    8. Approved by FDA for selected patients undergoing PCI, other procedures
  4. Mortality
    1. Reduces acute, 30 day, and 6 month death/MI by ~50% when used with stents [33,44]
    2. Overall mortality in PCI patients reduced ~20% [23]
  5. Early MI
    1. May be combined with reteplase and other thrombolytics or PCI in MI
    2. Half-dose reteplase + abciximab reduced early reinfarction rate but not 1 year mortality compared with full dose retaplase [11,56]
    3. Strongly consider in all patients treated with primary angioplasty + stent for MI [59]
  6. Patients with unstable angina, elevated troponin T, without MI treated with abciximab had ~75% reduction in MI [43]
  7. Stents + abciximab (anti-gp2B/3A) are cost effective (<7K/life year saved) compared with angioplasty + abciximab or stenting without abciximab [46]
  8. Abciximab is superior to tirofiban when used for elective or urgent PCI [82]
  9. In ACS without early revascularization, abciximab was not beneficial [57]

G. Eptifibatide (Integrilin®) [24,34,37]navigator

  1. Cyclic heptapeptide inhibitor of platelet gp IIb/IIIa
  2. Platelet blocking effects persist for ~4 hours after stopping infusion
    1. High dose double-bolus followed by infusion is now preferred
    2. Used in combination with heparin, ASA, and thienopyridine
  3. In unstable angina, reduced risk of death and nonfatal MI in men at 30 days [34]
  4. FDA approved for ACS or PCTA
  5. ESPIRIT Studies [54,55]
    1. Patients undergoing elective PCI
    2. Eptifibatide double bolus with infusion for elective PCI + stenting reduced 30 day death + MI + early target vessel revascularization >30% [54,55]
    3. Eptifibatide reduced 1 year death+MI by 37% in patients with elective stenting [89]
    4. Eptifibatide improves clinical outcomes in patients with or without diabetes [64]
  6. Very small increase on overall bleeding rates but not in hemorrhagic stroke
  7. Priced less than abciximab, more than tirofiban [64]

H. Other Glycoprotein IIb/IIIa Inhibitors navigator

  1. Tirofiban (Aggrastat®) [37]
    1. Peptide inhibitor of platelet gp 2b/3a given IV
    2. Tirofiban shows efficacy when added to aspirin [28] and aspirin plus heparin [29] in patients with unstable angina and non-Q wave MI
    3. Tirofiban + aspirin was not as effective as heparin + aspirin overall in ACS [29]
    4. Tirofiban more effective than heparin (both with aspirin) in patients with ACS and elevated troponin I or T concentrations [45]
    5. In stenting, abciximab was superior to tirofiban at 30 days [58] but similar outcomes occurred at 6 months [14]
    6. Tirofiban with PCI in acute ST-segment MI, improves TIMI Grade III flow, possibly clinical outcomes [12]
    7. Platelet blocking effects persist for ~4 hours after stopping infusion
    8. FDA approved for only ACS (not for elective PCI)
    9. Priced less than eptifibatide and abciximab
  2. Lamifiban
    1. Nonpeptide inhibitor of platelet glycoprotein 2b/3a
    2. Decreased incidence of MI and death in patients with unstable angina
  3. Sibrafiban [25,47]
    1. Novel, peptidomimetic selective gp2b/3a antagonist
    2. TIMI-12 results showed long-term platelet inhibition and efficacy
    3. No benefit over aspirin in patients with ACS [47]
    4. Major hemorrhage rates similar between aspirin and sibrafiban
    5. Minor, and moderate hemorrhage rates higher with sibrafiban
  4. Xemilofiban [9]
    1. Potent oral gp2b/3a inhibitor
    2. Reduces complications and death when used acutely in emergent PTCA
    3. Chronic therapy with xemilofiban for up to 6 months after PTCA adds no benefit

I. Antithrombin (AT, formerly Antithrombin III) navigator

  1. Naturally occuring serum protein which directly inhibits thrombin function
  2. Heparin is a cofactor for AT action
  3. Purified protein available for patients with congital and acquired deficiencies

J. Dipyridimole (Persantine®) navigator

  1. May stimulate prostacyclin synthesis
  2. When given intravenously, appears to block adenosine reuptake
  3. Adenosine causes coronary vasodilation and can be used as "pharmacologic stress" agent
  4. Rarely, may lead to AV block
  5. Weak anti-coagulant activity
  6. May be a useful adjunct to warfarin in patients with mechanical heart valves
  7. Used with aspirin reduces risk of recurrent stroke [70]
  8. Dose is 75-100mg po qid or 200mg po bid for adults

K. Experimental Antiplatelet Agentsnavigator

  1. Prasugrel [74]
    1. Novel thienopyridine related to clopidogrel
    2. Dose 60mg loading then 10mg daily
    3. Compared with standard clopidogrel in ACS, improved CV outcomes but increased bleeding
  2. Prostacyclin - vasodilator (PGI2) with platelet blocking activities
  3. Thromboxane A2 Blockers
  4. Platelet Activating Factor (PAF) Blockers

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